In the United States, Herpes Simplex Virus type 2 (HSV-2) is one of the most common sexually transmitted infections, affecting 16.2% of adults (Xu, F. et al., Seroprevalence of Herpes Simplex Virus Type 2 Among Persons Aged 14-49 Years—United States, 2005-2008, Centers for Disease Control and Prevention (2010)). HSV-2 infection can cause significant morbidity and mortality in neonates (Kimberlin, D. W., Herpes, 14:11-16 (2007)) and immune compromised hosts (Dupuis, S. et al., Nat. Genet., 33:388-391 (2003)). In addition, HSV-2 infection is the primary cause of genital lesions and has been linked to an increased risk of human immunodeficiency virus (HIV) acquisition (Freeman, E. E. et al., AIDS, 20:73-83 (2006); Wald, A., and K. Link, J. Infect. Dis., 185:45-52 (2002)). HSV-2 replicates in the genital epithelium, followed by retrograde axonal transport to the dorsal root ganglia where virus can remain and establish a lifelong, latent infection with periodic reactivation. What is striking, however, is that most HSV-2 infections are asymptomatic, and yet these individuals shed virus with high frequency. As a result, HSV-2 is commonly transmitted from individuals who have no history of genital lesions (Mertz, G. J., J. Infect. Dis., 198:1098-1100 (2008)). HSV-1 infection is also a significant cause of primary genital herpes disease and its incidence has been increasing in the U.S. and Europe (Wald, A. 2006. Genital HSV-1 infections. Sex Transm. Infect 82:189-190). Notably, in the negative control group of the Herpevac vaccine trial, HSV-1 had a higher attack rate for infection than did HSV-2 (3.2% vs. 1.5%, respectively) (Belshe, R. B., et al., Efficacy results of a trial of a herpes simplex vaccine. The New England Journal of Medicine, 2012. 366(1): p. 34-43.)
Without wishing to be bound by any theory, it is believed that the correlates of protective immunity against HSV-2 are unknown. Studies in HSV-2/HIV-1 co-infected individuals have shown that the loss of CD4+ T cells correlates with an increase in HSV-2 shedding (Schacker, T. et al., J. Infect. Dis., 178:1616-1622 (1998)). In addition, a prophylactic vaccine eliciting neutralizing antibody responses did not result in sterilizing immunity (Corey, L. et al., J. Amer. Med. Assoc., 282:331-340 (1999)). Human studies have also unveiled the role of CD8+ cytotoxic T cells in reducing HSV-2 replication and shedding. During primary infection, CD8+ T cells may prevent acute ganglion infection (Koelle, D. M., and L. Corey, Annu. Rev. Med., 59:381-395 (2008)). In addition, CD8+ T cells have been found to infiltrate genital lesions, correlating with viral clearance (Koelle, D. M. et al., J. Clin. Invest., 101:1500-1508 (1998)), and to accumulate at nerve endings in genital skin during HSV-2 reactivation (Zhu, J. et al., J. Exp. Med., 204:595-603 (2007)). In the commonly utilized HSV-2 mouse and guinea pig models, the roles of cellular immunity have been less defined or the data have been ambiguous. T cell depletion studies in the mouse have suggested a role for both CD4+ and CD8+ T in protection against intravaginal (i.vag.) HSV-2 challenge (Milligan, G. N., and D. I. Bernstein, Virology, 229:259-268 (1997); Milligan, G. N., D. I. Bernstein, and N. Bourne, J. Immunol., 160:6093-6100 (1998); Parr, M. B., and E. L. Parr, J. Virol., 72:2677-2685 (1998)). The T-cell mediated clearance of virus from the mucosa is largely dependent upon IFN-γ (Milligan, G. N., and D. I. Bernstein, Virology, 229:259-268 (1997)), and T cells activated in the absence of IFN-γ are not protective against HSV-2 infection (Johnson, A. J. et al., J. Reprod. Immunol., 84:8-15 (2010)).
Although many strategies have been tried, up to the present disclosure no successful HSV-2 vaccine has been developed (Koelle, D. M., and L. Corey, Annu. Rev. Med., 59:381-395 (2008)). The glycoproteins gD and gB have been widely used as vaccine antigens in order to generate neutralizing antibodies (Corey, L. et al., J. Amer. Med. Assoc., 282:331-340 (1999); Straus, S. E. et al., J. Infect. Dis., 176:1129-1134 (1997)). Tested in two clinical trials in HSV-2 discordant couples, the most promising vaccine candidate, manufactured by GlaxoSmithKline (GSK), was composed of a secreted gD protein formulated with MPL and alum; however, it was efficacious only in HSV-1 and -2 seronegative women (Stanberry, L. R. et al., N. Engl. J. Med., 347:1652-1661 (2002)). A subsequent Phase 3 study in 8,323 HSV-1 and -2 seronegative women (Herpevac trial) was not able to show significant protection against HSV-2 in this cohort. The secreted form of gD2 is truncated as a result of the deletion of the transmembrane domain (Higgins, T. J. et al., J. Infect. Dis., 182:1311-1320 (2000)). A previous study by Strasser et al. showed that, when compared to the full-length or cytosolic portion of gD2, the secreted form provided the best protection from acute disease in both mice and guinea pigs (Strasser, J. E. et al., J. Infect. Dis., 182:1304-1310 (2000)).
Replication-defective virus vaccines for HSV-2 are also in the clinical trial pipeline as they have been successful in animal models. UL5 (DNA helicase), UL29 (single-stranded DNA binding protein) are among the many proteins required for HSV-2 replication (Challberg, M. D., Proc. Natl. Acad. Sci. USA, 83:9094-9098 (1986); Knipe, D. M., Virus Res., 37:85-123 (1989)). A mutant virus lacking UL5 and UL29 has exhibited promising immunogenicity and subsequent protection in the mouse (Da Costa, X. et al., J. Virol., 74:7963-7971 (2000); Da Costa, X. J. et al., Proc. Natl. Acad. Sci. USA, 96:6994-6998 (1999)) and guinea pig models (Hoshino, Y. et al., J. Virol., 79:410-418 (2005); Hoshino, Y. et al., J. Infect. Dis., 200:1088-1095 (2009); Hoshino, Y. et al., Vaccine, 26:4034-4040 (2008)). In the past, inactivated HSV-2 vaccines also were tested in humans, but subsequently dismissed due to a lack of controls required for accurate data interpretation (reviewed in (Whitley, R. J., Herpes Simplex Viruses, p. 2461-2509. In D. M. Knipe and P. M. Howley (ed.), Fields Virology, Fourth ed, vol. 2. Lippincott Williams & Wilkins, Philadelphia (2001))). Provided herein are solutions to these and other problems in the art.